Inflammatory Bowel Disease or IBD refers to the chronic inflammation of the bowel wall and no direct cause has been identified for this disease at present. There are however several associative factors like stress, environment, microbial or genetic such as the mutation of the nucleotide oligomerizaton domain-containing protein 2 (NOD2) gene.
IBD has 2 main types: Crohn's disease (CD) and Ulcerative colitis (UC). Crohn's refers to the type in which the inflammation of the bowel appears to be in patches and can occur from anywhere in the gastrointestinal tract from mouth to anus, whereas, the inflammation in ulcerative colitis is more localised to the large intestine and appears to be continuous rather than in patches. The ulceration in UC also tends to be superficial while CD can affect the submucosa and muscularis layers of the bowel wall.
This blog will explore the various literature available to explain the pathophysiology of IBD using a systemtic literature search approach.
Literature search for Crohn's disease
Relevant full free text, books and documents from 2015 until January 2020 were searched using PubMed database. The keywords Crohn’s disease + pathophysiology were used to find search items related to Crohn’s disease pathophysiology. A total of 3965 search items were then narrowed down to include relevant items according to specified inclusion criteria using the database filters:
Year of publication between year 2015 (all months) and January 2020.
Human subjects filter
Title and abstract of article must discuss about Crohn’s disease pathophysiology, pathology or its pathogenesis.
Initially using numbers 1 & 2 of the inclusion criteria, the search was narrowed down to 298 searches and then narrowed down further to 12 as soon as inclusion criteria number 3 was applied. Upon assessing the remaining articles for its quality and relevance using the PROMPT criteria (Provenance, Relevance, Objectivity, Method, Presentation, and Timeliness), one (1) article about surgical interventions and another article which was not in English language were excluded thus narrowing the search further to 10 items.
Article selection process for Crohn’s disease pathophysiology
Literature Search for ulcerative colitis
A literature search was conducted using PubMed with the keywords: Ulcerative colitis + pathophysiology. Filters were also applied such as human species, full free text and books and documents dated between 2015 to 2020. Applying this search criteria led to 239 searches. Titles and abstracts of these search items were then reviewed to include only topics that discuss about ulcerative colitis pathophysiology, pathogenesis or pathology. Documents that were not in English were also excluded. A lot of the search items discussed about surgery and treatments and thus these were also excluded in the search. Overall, the items were then narrowed down to 8 documents.
Article selection process for ulcerative colitis pathophysiology
IBD Pathophysiology
The cause for both types of IBD (CD and UC) is still unknown (El-Salhy et al, 2016) however it is a widely accepted hypothesis that there are some associated factors. Anbazhagan et al (2018) mentions that it is associated to genetic, environmental, and microbiological factors.
Rampton and Shanahan (2008) emphasized that some genetic factors are specific to the type of IBD. There are a number of defective genes that are thought to be related to the incidence of IBD, however, the defect in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene is thought to have a very strong association with IBD. This gene is commonly mentioned in IBD genetic studies. Genetic associations on the NOD2 gene have been more common in Crohn’s disease but for ulcerative colitis, this remains controversial and further studies need to be conducted to conclude its association. Genetic risk factors can be detected with genome-wide association studies according to Gerhard et al (2018) and this was how variants of NOD2 DNA became the first identified genetic risk factor associated with Crohn’s disease.
NOD2 is specific to the inflammatory process in IBD because NOD2 polymorphisms can interact with the adaptor molecules and stimulate tumour necrosis factor receptor associated factor 6 (TRAF6) which results in the production of cytokines by activating the elements of the NF-kappa B (Elia et al, 2015) which is a protein that controls production of cytokines. When cytokines are released, this results to a cascade of events causing inflammation. This inflammatory process usually occurs in the body when exposed to infections or trauma.
Environment is also well emphasized to be an associated factor for the development of IBD. Zhou et al (2017) lists the following possible environmental factors for both Crohn’s disease and ulcerative colitis: smoking, medication, diet, quality of sleep, stress, physical activity, air pollution, ultraviolet exposure, low levels of vitamin D, appendectomy, and exposure to heavy metals. While this is a useful list, it is important to note that some factors may be strongly related to a specific IBD disease type such as smoking in which this is considered to be a possible environmental factor for Crohn’s disease than ulcerative colitis as mentioned by Whayman et al (2010). Identifying the possible factors are significant since some of these factors are modifiable such as stress, physical activity and exposure to chemicals in which management for IBD can also be focused on these areas. Managing IBD does not have to rely on medications alone but also on modifying the factors that may aggravate exacerbation such as stress as mentioned by Zhou et al (2017) wherein IBD is multifactorial and that the development of the disease is not just solely associated to genetic predispositions.
Other environmental factors associated to IBD also include the presence and balance of microorganisms. According to Langmead (2011), there are more than a hundred different species of bacteria that reside in the bowel. They play an important function by preventing infections from disease-causing bacteria but they also play a role in IBD development. The way the species of bacteria interact in the gut is significant in the control of inflammation.
In a meta-analysis conducted by Zhou et al (2016), low levels of a certain bacteria called bacteroides have been found to be associated to IBD. Nine (9) articles were examined and the findings suggest that the mean level of Bacteroides for both CD and UC patients in active disease were significantly lower. This is consistent with what Gherard et al (2018) mentions about the role of microbiota in IBD that an imbalance of intestinal flora results to immune system activation.
Bacteriodes is a gram-negative anaerobic bacteria normally found in some parts of the body such as the intestines, mouth, and genitals. Bacteriodes can express polysaccharide A, a carbohydrate molecule, which can induce cytokine production as well as the growth of regulatory T cells thus promoting inflammation and contributes greatly to the pathogenesis of disease like IBD (Zhou et al, 2016). T cells are lymphocytes that produce cytokines as its soluble mediator when presented with a target molecule on pathogens and toxins called an antigen. These cytokines attract other leucocytes such as phagocytes to migrate on the affected area causing immune reactions like inflammation (Male et al, 2012).
The convergence of genetic predispositions and the non-genetic factors like stress and diet can lead to dysbiosis in the intestines according to Sroufe et al (2017). The body’s bacterial handling is also thought to be affected by mutations in genes such as the mutations of IBD5, a genetic locus (Tozer et al, 2018). Also, the frequent inflammation that occurs in the intestinal mucosa in IBD can increase the gut’s susceptibility to infections due to the dysregulation of ion transport and impairment of the epithelial barrier. The inflammation also affects the epithelial cells lining the intestinal lumen which causes an imbalance in electrolyte absorption and secretion which can then result to diarrhoea, a hallmark symptom of IBD (Anbazhagan et al, 2018).
The inflammation that occurs in IBD is also a result of deregulated cytokine secretion and hyperactivity of the immune cells according to Gerhard et al (2018). Espaillat et al (2017) also explains that the dysregulation of immune cells contribute to ulcerative colitis pathogenesis. The neutrophils become unregulated leading to unnecessary activation. This promotes tissue injury and loss of homeostasis thus causing persistent inflammation. Whayman et al (2011) also mentions that proinflammatory cytokines are responsible for the inflammation of the bowel walls in IBD. The dysregulation of the cytokines are due to the breakdown of mucosal response balance by CD 4 T cells, mainly the Th1, Th2, and in some cases the Th17 type of T-cell.
Several cytokines are released when the activity of the CD4 T cells are dysregulated. Th2 dysregulation causes the release of interlukins such as interlukins-4, 5, 6 & 12 (IL-4, IL-5. IL-6, & IL-12). Interferon y, and tumour necrosis factor alpha (TNFα), are released by Th1 dysregulation (Whayman et al, 2011). The cytokine TNFα plays an important role in IBD because it is considered as one of the major cytokines that causes inflammation. In fact, certain biologics that act on this cytokine is already available such as infliximab which is a popular biologic for IBD.
There are several reasons for cytokine expression thus there are various ways to explain why inflammation occurs in IBD. This also explains why some IBD patients do not respond well to specific biologics because it probably did not target the specific cytokine involved. Exploring other types of biologics are sometimes necessary to find out the specific biologic that would work best for the patient. Other theories that explain the inflammatory process involved in IBD is about the binding of the α₄β₇ integrin of T cells to the mucosal vascular adressin cell adhesion molecule- 1 (MAdCAM-1) causing gastric mucosa infiltration. This infiltration causes inflammation of the bowel wall (Hahn et al, 2015). Integrins are a type of cell adhesion molecule (CAM) (Mitroulis et al, 2015). They bind to certain receptors and CAMS mediate cell-to-cell interactions which produces a response within the cell affecting the signalling and gene expression of cells (Horstkorte & Fuss, 2011). A₄β₇ is expressed on lymphocytes and they interact with MAdCAM-1 which is highly expressed in the bowel (Wittner et al, 2019). Some biologics target the α₄β₇ integrin by preventing its binding to MAdCAM-1 in which vedolizumab is an example of this biologic.
The dysregulated activity of cells and
the proinflammatory cytokines related to the
development of inflammatory
In terms of clinical manifestations, ulcerative colitis and Crohn’s disease are similar in the sense that both present with inflammation of the GI tract. The difference however is that inflammation in ulcerative colitis is more localised to the large intestine while Crohn’s disease can have patches of inflammation to different parts of the GI tract, from mouth to anus (Whayman et al, 2010). IBD can also exhibit extraintestinal manifestations such as oral lesions which is more common in Crohn’s disease. This is not fully understood however mucosal inflammation in the intestines triggers responses of the immune system by sharing epitopes (Muhvic-Urek et al, 2016) which can explain why inflammation outside the GI tract can occur especially in Crohn’s disease.
The clinical manifestations of IBD are almost the same for Crohn’s and ulcerative colitis. Both diseases present an increase in the frequency of bowel movements, abdominal cramping, abdominal pain, fever, body malaise and weight loss. It is important to also consider that each individual with IBD may present differently, with either just having one of the disease signs or a couple of them altogether. Some manifestations are specific to the disease type such as extraintestinal symptoms like oral lesions, uveitis or inflammation in the eye for Crohn’s. Since IBD is a chronic disease and there’s no cure up to this date, the key to managing IBD is in choosing the options that place the patient on a state of remission in order to improve quality of life and function as normal.
Where to next?
Inflammatory bowel disease is a complex disease and further studies are needed to determine the causes. It can be concluded from the literature that it is difficult to exactly distinguish which factors are the predisposing associative factors for a specific IBD disease type. This is also emphasised by Gerhard et al (2018) that there is a large overlap of risk factors between ulcerative colitis and Crohn’s disease especially genetic risk factors. Studying more about the causes would help greatly in managing the disease and hopefully also in finding the cure.
Disclaimer:
The content in this blog is for informational purposes only and should not be taken as medical advice. It is always best to consult your doctor for medical questions.
If you are a healthcare provider, the content here should not be used to make any diagnosis, give advice or prescribe treatment as this blog is for informational and educational purposes only. Healthcare is an everchanging field and each patient is unique. It is your responsibility as a healthcare provider to always refer to current care standards and practices.
References:
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